Pathogenesis of Hyperthyroidism

  • The natural history of a non-toxic multi nodular goiter (MNG):
    • Involves variable growth of individual nodules:
      • This may progress to hemorrhage and degeneration:
        • Followed by:
          • Healing and fibrosis
      • Calcification:
        • May be found in areas of previous hemorrhage
    • Some nodules may develop autonomous function:
      • Autonomous hyperactivity:
        • Is conferred by somatic mutations of thyrotropin or thyroid-stimulating hormone receptor (TSHR):
          • In 20% to 80% of toxic adenomas and some nodules of MNGs
        • Autonomously functioning nodules:
          • May become toxic in 10% of patients
        • Hyperthyroidism predominantly occurs:
          • When single autonomous nodules are larger than 2.5 cm in diameter:
            • However, in geographic areas with iodine deficiencysmaller autonomous nodules:
              • May produce systemic, clinical manifestations of hyperthyroidism
    • The development of hyperthyroidism in MNG takes many years:
      • The process evolves from:
        • A small gland with one small nodule or more to nodules increasing progressively in number, size, and function
      • Initially, most patients are euthyroid:
        • But with enlarging goiters, autonomy develops:
          • Illustrated by low or suppressed serum thyroid-stimulating hormone (TSH) with normal serum levels of thyroid hormones
  • Graves’ disease:
    • Is a syndrome that consists of:
      • Hyperthyroidism
      • Goiter
      • Ophthalmopathy (orbitopathy)
      • Occasionally a dermopathy referred to as:
        • Pretibial or localized myxedema
    • Hyperthyroidism:
      • Is the most common feature of Graves’ disease:
        • Affecting nearly all patients
      • It is caused by autoantibodies to the TSHR (TSHR-Ab):
        • That activate the receptor:
          • Thereby stimulating thyroid hormone synthesis and secretion:
            • As well as thyroid growth:
              • Causing a diffuse goiter
    • The histology of the thyroid gland in patients with Graves’ hyperthyroidism:
      • Is characterized by:
        • Follicular hyperplasia
        • A patchy (multifocal) lymphocytic infiltration
        • Rare lymphoid germinal centers:
          • The majority of intra-thyroidal lymphocytes are:
            • T cells:
              • Germinal centers (B cells) are much less common than in chronic autoimmune thyroiditis (Hashimoto’s disease)
        • Thyroid epithelial cell size:
          • Correlates with the intensity of the lymphocytic infiltrate:
            • Suggesting thyroid cell stimulation by local B cells secreting TSHR-Ab
      • The presence of TSHR-Ab antibodies:
        • Is positively correlated with:
          • Active diseaseand with relapse of the disease
    • There is an underlying genetic predisposition:
      • Because of an increased frequency of haplotypes human leukocyte antigen:
        • HLA-B8 and HLA-DRw3 in white patients
        • HLA-Bw36 in Japanese patients
        • HLA-Bw46 in Chinese patients
      • However, it is not clear what triggers the acute episodes:
        • Some factors that may incite the immune response are:
          • Pregnancy:
            • Particularly the postpartum period
          • Iodine excess:
            • Particularly in geographic areas of iodine deficiency
        • Lithium therapy
        • Viral or bacterial infections
        • Glucocorticoid withdrawal
    • The etiology and pathogenesis of Graves’ ophthalmopathy are not known:
      • It may involve cytotoxic lymphocytes and cytotoxic antibodies:
        • Sensitized to a common antigen found in:
          • Orbital fibroblasts, orbital muscle, and thyroid tissue:
            • Which may cause inflammation:
              • Resulting in proptosis of the globes
      • It has been suggested recently that TSHR-bearing circulating fibroblasts and fibrocytes:
        • May be activated directly by the TSHR-Ab
    • The pathogenesis of dermopathy may also involve this mechanism:
      • Patients with exophthalmos and particularly those with dermopathy:
        • Almost always have high titers of circulating TSHR autoantibodies:
          • Suggesting that these two clinical manifestations represent the most severe form of this disease

#Arrangoiz #CancerSurgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #ThyroidExpert #SurgicalOncologist #EndocrineSurgery #MountSinaiMedicalCenter #Miami #ThyroidNodule #ToxicNodularGoiter #TNG #MultinodularGoiter #GravesDisease #Hyperthyroidism #Goiter

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